A kind of preparation device and method of polylactic acid-glycolic acid block copolymer

Abstract

The present invention discloses a preparation device and method of a polylactic acid-glycolic acid block copolymer. The device comprises a first reactor, a second reactor, a first film scraper, a second film scraper, and a third reaction unit and a viscosity increasing device connected in sequence in a material feeding direction; the discharge port of the first reactor is connected to the feed port of the first film scraper through a material conveying pipeline, and the discharge port of the second reactor is connected to the feed port of the second film scraper through a material conveying pipeline; the discharge port of the first film scraper and the discharge port of the second film scraper are respectively connected to the feed port of the third reaction unit through a material conveying pipeline.

Description

Technical Field

[0001] The invention relates to the field of chemical industry, and in particular to a device for continuously preparing PLGA block copolymers and a preparation method based on the device. Background Art

[0002] Polylactic-glycolic acid (PLGA) is a biodegradable polymer material that is non-toxic, has good biocompatibility, a high degradation rate in the body, and its degradation products can participate in the metabolic cycle of the body. Therefore, PLGA has good development potential in the fields of biomedicine and other materials. At present, the method for preparing PLGA based on the ring-opening polymerization process is usually to melt-mix glycolide and lactide directly in a reactor, and then perform ring-opening polymerization under high temperature and high vacuum conditions. The PLGA obtained in this way is a random copolymer, and the combination of glycolide segments and lactide segments in its molecular chain segments is disorderly, resulting in unstable quality of the resulting copolymer product. For example, in the process of preparing PLGA, it is usually necessary to carry out a ring-opening polymerization reaction at a high temperature (for example, 200-220°C), and to carry out devolatilization at a further elevated temperature (for example, 220-240°C), which can easily lead to thermal oxidative degradation of the generated PLGA molecular segments. The generated free radicals will induce the oxidation and deterioration of glycolide, lactide and their oligomers that have not been bonded to the PLGA molecular chains in the reaction system and remain in the final PLGA product. This will have a relatively serious negative impact on the color quality, heat aging resistance, degradation stability, etc. of the final molded product, which greatly limits the use of PLGA.

[0003] Therefore, there is an urgent need in the art to provide a device and method for obtaining PLGA with good performance, for example, better color quality, better thermal aging resistance and / or more degradation stability. Summary of the invention

[0004] The present invention aims to provide a preparation device and a corresponding method for a polylactic acid-glycolic acid block copolymer.

[0005] In a first aspect of the present invention, a device for preparing polylactic acid-glycolic acid block copolymer is provided, the device comprising a first reactor, a second reactor, a first film scraper, a second film scraper, and a third reaction unit and a viscosity increasing device sequentially connected in a material feeding direction;

[0006] The discharge port of the first reactor is connected to the feed port of the first scraper through a material conveying pipeline, and the discharge port of the second reactor is connected to the feed port of the second scraper through a material conveying pipeline; the discharge port of the first scraper and the discharge port of the second scraper are respectively connected to the feed port of the third reaction unit through material conveying pipelines.

[0007] In another embodiment, the first film scraper and the second film scraper both contain a shell; the interior of the shell is provided with a rotating shaft, a plurality of scrapers radially connected to the rotating shaft, and a film spreader connected to the feed port; the film spreader is located above the scraper closest to the top of the shell.

[0008] In another embodiment, the distance between the outer side surface of the scraper and the inner wall of the shell is not greater than 5 mm; preferably not greater than 2 mm.

[0009] In another embodiment, the first film scraper and the second film scraper both further include a heating element disposed outside the housing; preferably an electric heating jacket.

[0010] In another embodiment, a gas outlet is provided on the top of the shell, and the level of the gas outlet is higher than the level of the feed inlet;

[0011] The device also includes a first raw material collecting unit and a second raw material collecting unit, wherein the first raw material collecting unit is connected to the air outlet of the first scraper through a material conveying pipeline, and the second raw material collecting unit is connected to the air outlet of the second scraper through a material conveying pipeline.

[0012] In another embodiment, the first raw material collection unit and the second raw material collection unit each contain a gas-liquid separator, a condenser and a recovery tank in sequence according to the material feeding direction.

[0013] In another embodiment, a vacuum pump is provided between the gas-liquid separator and the condenser.

[0014] In another embodiment,

[0015] A melt pump is provided on a material conveying pipeline connecting the discharge port of the first reactor and the feed port of the first scraper;

[0016] And / or, a melt pump is provided on the material conveying pipeline connecting the discharge port of the second reactor and the feed port of the second scraper;

[0017] And / or, a melt pump is provided on the material conveying pipeline connecting the discharge port of the first scraper and the feed port of the third reaction unit;

[0018] And / or, a melt pump is provided on the material conveying pipeline connecting the discharge port of the second scraper and the feed port of the third reaction unit;

[0019] And / or, the discharge port of the third reaction unit is connected to the feed port of the viscosity increasing device via a material conveying pipeline, and a melt pump is provided on the material conveying pipeline.

[0020] In another embodiment, the third reaction unit is selected from a static mixer or a third reactor, and the third reactor is connected to an ester exchange catalyst sending unit.

[0021] In another embodiment, the transesterification catalyst sending unit comprises a transesterification catalyst storage tank and a material conveying pipeline connecting the transesterification catalyst storage tank and the third reactor, and a metering pump is provided on the material conveying pipeline.

[0022] In a second aspect of the present invention, a method for preparing a polylactic acid-glycolic acid block copolymer is provided, the method comprising the steps of:

[0023] (1) polymerizing glycolide and lactide in a first reaction kettle and a second reaction kettle to obtain a glycolide prepolymer and a lactide prepolymer, respectively;

[0024] (2) allowing the obtained glycolide prepolymer to enter a first scraper for pre-devolatilization treatment, and allowing the obtained lactide prepolymer to enter a second scraper for pre-devolatilization treatment;

[0025] (3) allowing the materials that have been pre-devolatilized in the first scraper and the second scraper to enter the third reaction unit for copolymerization to obtain a polylactic acid-glycolic acid prepolymer; and

[0026] (4) subjecting the polylactic acid-glycolic acid prepolymer to final polymerization and devolatilization in a viscosity increasing device to obtain a polylactic acid-glycolic acid block copolymer.

[0027] In another embodiment, in step (1), the polymerization temperature of glycolide to obtain glycolide prepolymer is 130-190°C; and / or the polymerization temperature of lactide to obtain lactide prepolymer is 120-180°C.

[0028] In another embodiment, step (1) obtains a glycolide prepolymer with a relative molecular weight of 12,000-40,000; and / or obtains a lactide prepolymer with a relative molecular weight of 12,000-40,000.

[0029] In another embodiment, the third reaction unit in step (3) is a static mixer, and the static mixer adopts at least two stages of gradient temperature increase, the temperature range of the first stage is between 160-200°C, and the temperature range of the last stage is between 190-230°C.

[0030] In another embodiment, the third reaction unit in step (3) is a third reaction kettle, and an ester exchange catalyst is added to the third reaction kettle.

[0031] In another embodiment, the transesterification catalyst is selected from at least one of a titanate catalyst, an organotin catalyst, and an alkali metal alkyl oxide catalyst; preferably a titanate catalyst; more preferably tetrabutyl titanate and / or tetraisopropyl titanate, and the amount of the transesterification catalyst added is 0.5-5wt% of the total mass of the material discharged from the first scraper and the second scraper.

[0032] In another embodiment, the temperature of the third reactor is controlled in the range of 180-210° C. to a value that the difference of the intrinsic viscosity of the material in the third reactor at 30±5 minutes is not more than 6, and the temperature of the third reactor is increased to a range of 190-230° C. to a value that the difference of the intrinsic viscosity of the material in the third reactor at 10±3 minutes is not more than 1.5.

[0033] Accordingly, the present invention provides an apparatus and method for obtaining PLGA with good performance, wherein the obtained PLGA has better color quality, better heat aging resistance and / or is more stable to degradation. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is a schematic diagram of PLGA preparation device I in device example 1.

[0035] Figure 2 It is a schematic diagram of PLGA preparation device II in device example 2. DETAILED DESCRIPTION

[0036] After extensive and in-depth research, the inventors found that glycolide (GA) prepolymer and lactide (LA) prepolymer can be prepared separately, and then the prepolymers are pre-devolatilized separately, and then a static mixer or a reactor (preferably in combination with an ester exchange catalyst) is used to perform copolymerization to obtain PLGA. On this basis, the present invention was completed.

[0037] As used in the present invention, "feed direction" refers to the direction in which the reaction materials or the materials to be processed move forward.

[0038] As used in the present invention, "couple" refers to two or more devices being operatively connected to each other and having an interaction and mutual influence relationship with each other.

[0039] As used in the present invention, "film distributor" refers to a film distributor that helps liquid materials to be evenly distributed on the inner wall of each heating tube of a heat exchange tube (a heater), or evenly distributed on the inner wall of a reactor, and descend in a uniform film shape.

[0040] In the present invention, "polylactic acid-glycolic acid block copolymer" and "PLGA" can be used interchangeably, both referring to a polymer formed by connecting polylactic acid and polyglycolic acid segments together, with a molecular weight of 5w-30w, a melting point of 150-220°C, an intrinsic viscosity of 0.1-2.0dl / g, and can be controlled to obtain crystalline polymers and amorphous polymers.

[0041] PLGA preparation device

[0042] The invention provides a device for continuously preparing PLGA, comprising a first reactor for preparing a GA prepolymer, a second reactor for preparing a LA prepolymer, a first scraper connected to the first reactor and used for pre-devolatilization of the GA prepolymer from the first reactor, a second scraper connected to the second reactor and used for pre-devolatilization of the LA prepolymer from the second reactor, a third reaction unit connected to the first scraper and the second scraper respectively and used for copolymerizing the GA prepolymer with the LA prepolymer to obtain the PLGA prepolymer, and a viscosity-increasing device for final polymerization and devolatilization of the PLGA prepolymer from the third reaction unit.

[0043] The material conveying pipeline between the first reactor and the first scraper, the material conveying pipeline between the second reactor and the second scraper, the material conveying pipeline between the first scraper and the third reaction unit, the material conveying pipeline between the second scraper and the third reaction unit, and the material conveying pipeline between the third reaction unit and the viscosity increasing device are all equipped with conventional heat tracing to make the materials conveyed therein in a state of melt flow. In addition, a melt pump of appropriate model / power can be selected according to the reaction time of the raw material monomers in each reactor, the volume of each material conveying pipeline, and the time for the material to pass through the third reaction unit to ensure the smooth progress of continuous production.

[0044] In one embodiment of the present invention, the third reaction unit is a static mixer; for example, but not limited to, a SK type static mixer, a SX type static mixer, a SV type static mixer, and the like.

[0045] In one embodiment of the present invention, the third reaction unit is a third reactor. In a preferred embodiment, the third reactor is connected to an ester exchange catalyst storage tank, and a metering pump is provided on the connecting pipeline between the third reactor and the ester exchange catalyst storage tank for accurately adding the ester exchange catalyst to the third reactor.

[0046] The reaction kettle used in the present invention comprises a shell, a stirring paddle inserted in the shell, and a heating element for supplying heat to the shell.

[0047] As conventionally used, the stirring paddle inserted in the shell can be suspended and not in contact with the inner wall and the bottom of the shell; in one embodiment of the present invention, the stirring paddle is driven by a driving motor to achieve the stirring function.

[0048] The heating element is preferably a heat exchanger arranged on the inner wall of the shell along the axial direction of the shell.

[0049] The upper portion of the shell is provided with a feed inlet, and the bottom portion is provided with a discharge port. In one embodiment of the present invention, a solenoid valve may be provided at the discharge port.

[0050] In one embodiment of the present invention, the bottom of the shell is in an arc shape.

[0051] The film scraper used in the present invention comprises a shell, a rotating shaft inserted into the inner cavity of the shell along the axial direction of the shell, a plurality of scrapers arranged on the rotating shaft along the axial direction of the shell and spaced apart from each other, and a heating element (such as but not limited to an electric heating sleeve) arranged on the outer side of the shell, and a film spreader is also arranged on the scraper closest to the top of the shell, wherein the film spreader can be a conventional film spreader for a scraped film evaporator or reactor on the market, and no special structural modification is required. The rotating shaft is generally driven by a drive motor connected to it.

[0052] A scraper may be provided in the radial direction of the rotating shaft, or a scraper may be provided at each radial end. The number of scrapers is usually determined by the inner cavity space of the shell; the radial distance between the outer side of the scraper and the rotating shaft is determined by the cross-sectional size of the shell. In one embodiment of the present invention, a gap of no more than 5 mm, preferably no more than 2 mm, is left between the outer side of the scraper and the inner wall of the shell. The thickness of the scraper may be that used in a conventional wiped film evaporator or reactor.

[0053] The top of the shell is provided with a feed inlet and an air outlet, and the feed inlet is connected to the film distributor, and the air outlet is connected to the inner cavity of the shell. Preferably, the air outlet is located at a higher level than the feed inlet.

[0054] A discharge port is provided at the bottom of the shell body, and a solenoid valve may be provided at the discharge port.

[0055] The film scraper used in the present invention is also connected to a raw material collection unit; the raw material collection unit comprises a gas-liquid separator, a condenser and a raw material recovery tank which are sequentially connected to the film scraper.

[0056] A vacuum pump may be arranged between the gas-liquid separator and the condenser to evacuate the scraper, so that the lactide monomers that have not participated in the reaction and have been separated from the slurry film can be promptly extracted and collected.

[0057] The exhaust port of the gas-liquid separator is connected to the material inlet of the condenser through a pipeline, and the material outlet of the condenser is connected to the raw material collection tank through a pipeline (provided with a delivery pump).

[0058] The gas-liquid separator adopts side-line feeding, and a liquid foam entrainment prevention device is provided at the inner upper part of the gas-liquid separator. Preferably, the liquid foam entrainment prevention device is a wire mesh or a cyclone sheet.

[0059] Under working condition, the material from the reactor enters the scraper shell from the feed port, and the material is distributed to the inner wall of the scraper shell through the film distributor. The rotating scraper scrapes the material continuously and evenly on the inner wall of the scraper shell into a slurry film of uniform thickness, and pushes it downward in a spiral shape. In this process, the rotating scraper ensures that the continuous and uniform slurry film produces high-speed turbulence, and prevents the slurry film from coking and scaling on the inner wall of the scraper shell. The lactide monomers remaining in the slurry film and not participating in the reaction are separated from the slurry film in the form of gas phase and move upward, and are discharged from the gas outlet and recovered by the raw material collection unit.

[0060] The "viscosity-enhancing device" in the present invention plays a devolatilization role, which can promote the further polymerization of the PLGA prepolymer and remove the generated small molecules from the system in time, so that the molecular weight of the polymer is further improved, and the corresponding polymer viscosity will also be further increased; the "viscosity-enhancing device" in the present invention can be, for example but not limited to, a twin-screw extruder with only a devolatilization section.

[0061] PLGA Preparation Method

[0062] The present invention provides a method for preparing PLGA, which is carried out by the above-mentioned preparation device and comprises the steps of:

[0063] In the first step, glycolide and lactide are reacted in a first reaction kettle and a second reaction kettle respectively containing a catalyst to obtain a glycolide prepolymer and a lactide prepolymer respectively;

[0064] In the second step, the glycolide prepolymer obtained in the first reaction kettle is fed into a first scraper for pre-devolatilization treatment, and the lactide prepolymer obtained in the second reaction kettle is fed into a second scraper for pre-devolatilization treatment;

[0065] The third step is to allow the pre-devolatilized materials from the first scraper and the second scraper to enter the third reaction unit for copolymerization to obtain PLGA prepolymer;

[0066] The fourth step is to subject the polylactic acid-glycolic acid prepolymer to final polymerization and devolatilization in a viscosity increasing device to obtain PLGA.

[0067] In the first step, the glycolide and lactide used as raw materials only need to enter different reaction kettles, and the obtained prepolymer enters the corresponding scraper connected to the reaction kettle in the second step.

[0068] For the convenience of description, the present invention adopts the description method of the first reaction kettle and the second reaction kettle, and the film scrapers connected thereto are described as the first film scraper and the second film scraper.

[0069] In one embodiment of the present invention, the first step is to polymerize glycolide in the first reaction kettle at 130-190° C. in the presence of a catalyst to obtain a glycolide prepolymer with a relative molecular weight of 12,000-40,000.

[0070] In one embodiment of the present invention, in the first step, in the second reaction kettle, in the presence of a catalyst, lactide is polymerized at 120-180° C. to obtain a lactide prepolymer with a relative molecular weight of 12,000-40,000.

[0071] The reaction in the first step is carried out under normal pressure.

[0072] The catalyst used in the first step can be selected from at least one of tin compounds, antimony compounds or zinc compounds, such as but not limited to one or more of the following: stannous octoate, stannous chloride, tin lactate, antimony trioxide, diethyl zinc and zinc acetate dihydrate.

[0073] In one embodiment of the present invention, in the first step, the amount of the catalyst is between 0.001-0.3 wt % based on the total weight of the raw materials in the reactor.

[0074] In one embodiment of the present invention, the molar ratio of glycolide to lactide entering the first reaction kettle and the second reaction kettle respectively in the first step is 10-90:90-10.

[0075] In the above second step, the glycolide prepolymer and the lactide prepolymer enter the corresponding scraper at a feed rate of 0.2-2.0 kg / hour; in one embodiment of the present invention, the speed at which the glycolide prepolymer and the lactide prepolymer enter each corresponding scraper is basically the same.

[0076] In the above second step, the absolute pressure in the scraper is generally about 10-100 kPa, the inner wall temperature is generally about 150-220° C., and the speed of the scraper is about 50-150 rpm.

[0077] In the above second step, the material entering the scraper is distributed to the inner wall of the scraper through the film distributor, and the scraper continuously and evenly scrapes the material on the inner wall of the scraper into a liquid film of uniform thickness, and pushes it downward in a spiral shape; in this process, the rotating scraper ensures that the continuous and uniform slurry film produces high-speed turbulence, and prevents the slurry film from coking and scaling on the inner wall of the scraper shell, while the lactide monomers remaining in the slurry film and not participating in the reaction are separated from the slurry film in the form of gas phase and move upward, and are discharged from the gas outlet and recovered by the raw material collection unit.

[0078] In one embodiment of the present invention, the average film thickness of the first film scraper is about 200-1000 μm, and the average film thickness of the second film scraper is about 300-900 μm. The average film thickness of the two film scrapers may be the same.

[0079] The third step enables the materials discharged from the first scraper and the second scraper to be simultaneously transported to the third reaction unit.

[0080] In one embodiment of the present invention, the third reaction unit is a static mixer, in which the temperature is gradually increased in at least two stages, the temperature range of the first stage can be between 160-200°C, and the temperature range of the last stage can be between 180-220°C; the time taken for the material to pass through each stage also increases gradually, for example but not limited to, the time taken to pass through the first stage is 5-40 minutes, and the time taken to pass through the last stage can be 40-70 minutes.

[0081] The internal pressure of the static mixer used in the above third step is normal pressure.

[0082] In one embodiment of the present invention, the third reaction unit is a third reactor, and the amount of the transesterification catalyst added to the third reactor is 0.5-5wt% based on the total weight of the materials from the first scraper and the second scraper. The transesterification catalyst is selected from at least one of a titanate catalyst, an organotin catalyst, and an alkali metal alkyl oxide catalyst; preferably a titanate catalyst; more preferably tetrabutyl titanate and / or tetraisopropyl titanate.

[0083] In one embodiment of the present invention, in the third step, the temperature of the third reactor is first controlled to about 180-210°C for reaction until the difference in the intrinsic viscosity of the material in the third reactor is no more than 6 at about 30±5 minutes, and then the temperature of the third reactor is increased to about 190-230°C for further reaction until the difference in the intrinsic viscosity of the material in the third reactor is no more than 1.5 at about 10±3 minutes, thereby obtaining a PLGA prepolymer.

[0084] The temperature for final polymerization and devolatilization in the fourth step is about 200-240° C., the absolute pressure is about 150-600 Pa, and the devolatilization time is about 0.5-2 hours to obtain a PLGA copolymer.

[0085] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.

[0086] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0087] In this document, all features defined in the form of numerical ranges or percentage ranges, such as values, quantities, contents and concentrations, are for simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible sub-ranges and individual values ​​within the range (including integers and fractions).

[0088] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate values, the relevant numerical values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value is inherently inevitably subject to standard deviations due to individual test methods. Here, "about" generally refers to the actual value within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range. Alternatively, the term "about" represents that the actual value falls within the acceptable standard error of the mean value, depending on the consideration of those skilled in the art. Except for the experimental examples, or unless otherwise explicitly stated, it is understood that all ranges, quantities, values ​​and percentages used herein (for example, to describe the amount of material, the length of time, temperature, operating conditions, quantitative ratios and other similar ones) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the attached claims are all approximate values ​​and can be changed as needed. At least these numerical parameters should be understood as the indicated significant digits and the values ​​obtained by applying the general rounding method.

[0089] The above-mentioned features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in combination with any combination form. As long as there is no contradiction in the combination of these features, all possible combinations should be considered to be within the scope of this specification. Each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0090] The main advantages of the present invention are:

[0091] 1. The present invention adopts a scraper to pre-devolatilize the obtained GA prepolymer and LA prepolymer, which greatly reduces the content of lactide monomer or oligomer of lactide monomer in the prepolymer. The color quality of the obtained PLGA copolymer product overcomes the yellowing problem of the PLGA product obtained by the existing preparation process.

[0092] 2. The present invention can continuously prepare PLGA copolymers. During the preparation process, local coking will not occur due to long-term overheating of materials in the reactor, which reduces the loss of reaction materials, is conducive to improving production efficiency, and is suitable for mass production.

[0093] 3. The present invention adopts a raw material collection unit to recover the lactide monomers or oligomers of the lactide monomers that have not participated in the reaction. After purification, they can continue to be used as reaction raw materials, thereby reducing the loss of reaction materials and causing no environmental pollution during the production process.

[0094] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not indicated in the following examples are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions, or parts are by weight. The units in the weight volume percentages in the present invention are well known to those skilled in the art, for example, refer to the weight (grams) of the solute in 100 ml of solution. Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the recorded content can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0095] Device Example 1

[0096] Provide as attached Figure 1 The PLGA preparation device shown.

[0097] The PLGA preparation device I includes a first reactor 1000A, a second reactor 1000B, a first film scraper 2000A, a second film scraper 2000B, a static mixer 3000A and a viscosity increasing device 4000; the discharge port 1400 at the bottom of the shell 1600 of the first reactor 1000A is connected to the feed port 2030 at the top of the shell 2080 of the first film scraper 2000A through a material conveying pipeline, and the discharge port 1400 at the bottom of the shell 1600 of the second reactor 1000B is connected to the feed port 2030 at the top of the shell 2080 of the first film scraper 2000A through a material conveying pipeline. The feed port 1400 is connected to the feed port 2030 at the top of the shell 2080 of the second scraper 2000B through a material conveying pipeline; the discharge port 2040 at the bottom of the shell 2080 of the first scraper 2000A and the second scraper 2000B are respectively connected to the feed port 3100 of the static mixer 3000A through the material conveying pipeline, and the discharge port 3200 of the static mixer 3000A is connected to the feed port 4100 of the viscosity increasing device 4000 through the material conveying pipeline.

[0098] The first reactor 1000A and the second reactor 1000B both include a shell 1600, a feed port 1300 disposed at the top of the shell 1600, a discharge port 1400 disposed at the bottom of the shell 1600, a stirring paddle 1100 suspended in the shell, and a heat exchanger 1200 disposed inside the shell 1600; the stirring paddle 1100 can be connected to a driving motor 1500.

[0099] The first film scraper 2000A and the second film scraper 2000B are respectively connected to a raw material collection unit 2100. The raw material collection unit 2100 contains a gas-liquid separator 2110, a condenser 2120 and a recovery tank 2130; the first film scraper 2000A and the second film scraper 2000B are respectively connected to the gas-liquid separator 2110 in the raw material collection unit 2100 through the gas outlet 2050 set at the top of the shell 2080 through the material conveying pipeline, the top of the gas-liquid separator 2110 is connected to the inlet of the condenser 2120 through the material conveying pipeline, and the outlet of the condenser 2120 is connected to the recovery tank 2130 through the material conveying pipeline; a vacuum pump 200 is set on the material conveying pipeline connecting the gas-liquid separator 2110 and the condenser 2120.

[0100] The first film scraper 2000A and the second film scraper 2000B both comprise a housing 2080, a rotating shaft 2060, a scraper 2010 radially connected to the rotating shaft and with its outer side parallel to the rotating shaft, a feed port 2030 and an air outlet 2050 respectively arranged at the top of the housing 2080, a discharge port 2040 arranged at the bottom of the housing 2080, and an electric heating sleeve 2070 arranged outside the housing 2080; a film spreader 2020 is arranged inside the housing 2080 at a position higher than the scraper 2010. The distance between the outer side of the scraper 2010 and the inner wall of the housing 2080 is about 0-5 mm, preferably not more than 2 mm; the rotating shaft 2060 can be connected to a driving motor 1500.

[0101] A melt pump 100 is arranged on the material conveying pipeline connecting the discharge port 1400 at the bottom of the shell 1600 of the first reactor 1000A and the feed port 2030 at the top of the shell 2080 of the first scraper 2000A; a melt pump 100 is arranged on the material conveying pipeline connecting the discharge port 1400 at the bottom of the shell 1600 of the second reactor 1000B and the feed port 2030 at the top of the shell 2080 of the second scraper 2000A; melt pumps 100 are respectively arranged on the material conveying pipelines connecting the discharge port 2040 at the bottom of the shell 2080 of the first scraper 2000A and the second scraper 2000B and the feed port 3100 of the static mixer 3000A; a melt pump 100 is arranged on the material conveying pipeline connecting the discharge port 3200 of the static mixer 3000A and the feed port 4100 of the viscosity increasing device 4000.

[0102] Device Example 2

[0103] Provide as attached Figure 2 The PLGA preparation device shown.

[0104] PLGA preparation device II includes a first reactor 1000A, a second reactor 1000B, a first film scraper 2000A, a second film scraper 2000B, a third reactor 1000C and a viscosity increasing device 4000; the discharge port 1400 at the bottom of the shell 1600 of the first reactor 1000A is connected to the feed port 2030 at the top of the shell 2080 of the first film scraper 2000A through a material conveying pipeline, and the discharge port 1400 at the bottom of the shell 1600 of the second reactor 1000B is connected to the feed port 2030 at the top of the shell 2080 of the first film scraper 2000A through a material conveying pipeline. The material conveying pipeline is connected to the feed port 2030 at the top of the shell 2080 of the second scraper 2000B; the discharge port 2040 at the bottom of the shell 2080 of the first scraper 2000A and the second scraper 2000B is respectively connected to the two feed ports 1300 at the top of the shell 1600 of the third reactor 1000C through the material conveying pipeline, and the discharge port 1400 at the bottom of the shell 1600 of the third reactor 1000C is connected to the feed port 4100 of the viscosity increasing device 4000 through the material conveying pipeline.

[0105] The first reactor 1000A, the second reactor 1000B and the third reactor 1000C all include a shell 1600, a feed port 1300 disposed at the top of the shell 1600, a discharge port 1400 disposed at the bottom of the shell 1600, a stirring paddle 1100 suspended in the shell, and a heat exchanger 1200 disposed inside the shell 1600; the stirring paddle 1100 can be connected to a driving motor 1500.

[0106] The first film scraper 2000A and the second film scraper 2000B are respectively connected to a raw material collection unit 2100. The raw material collection unit 2100 contains a gas-liquid separator 2110, a condenser 2120 and a recovery tank 2130; the first film scraper 2000A and the second film scraper 2000B are respectively connected to the gas-liquid separator 2110 in the raw material collection unit 2100 through the gas outlet 2050 set at the top of the shell 2080 through the material conveying pipeline, the top of the gas-liquid separator 2110 is connected to the inlet of the condenser 2120 through the material conveying pipeline, and the outlet of the condenser 2120 is connected to the recovery tank 2130 through the material conveying pipeline; a vacuum pump 200 is set on the material conveying pipeline connecting the gas-liquid separator 2110 and the condenser 2120.

[0107] The first film scraper 2000A and the second film scraper 2000B both comprise a housing 2080, a rotating shaft 2060, a scraper 2010 radially connected to the rotating shaft and with its outer side parallel to the rotating shaft, a feed port 2030 and an air outlet 2050 respectively arranged at the top of the housing 2080, a discharge port 2040 arranged at the bottom of the housing 2080, and an electric heating sleeve 2070 arranged outside the housing 2080; a film spreader 2020 is arranged inside the housing 2080 at a position higher than the scraper 2010. The distance between the outer side of the scraper 2010 and the inner wall of the housing 2080 is about 0-5 mm, preferably not more than 2 mm; the rotating shaft 2060 can be connected to a driving motor 1500.

[0108] The third reactor 1000C is connected to a transesterification catalyst delivery unit 1700. The transesterification catalyst delivery unit 1700 comprises a transesterification catalyst storage tank 1710 and a metering pump 1720 provided on a material delivery pipeline connecting the transesterification catalyst storage tank 1710 and the shell 1600 of the third reactor 1000C.

[0109] A melt pump 100 is provided on a material conveying pipeline connecting the discharge port 1400 at the bottom of the shell 1600 of the first reactor 1000A and the feed port 2030 at the top of the shell 2080 of the first scraper 2000A; a melt pump 100 is provided on a material conveying pipeline connecting the discharge port 1400 at the bottom of the shell 1600 of the second reactor 1000B and the feed port 2030 at the top of the shell 2080 of the second scraper 2000A; respectively Melt pumps 100 are respectively provided on the material conveying pipelines connecting the discharge port 2040 at the bottom of the shell 2080 of the first scraper 2000A and the second scraper 2000B and the feed port 1300 at the top of the shell 1600 of the third reactor 1000C; a melt pump 100 is provided on the material conveying pipeline connecting the discharge port 1400 of the shell 1600 of the third reactor 1000C and the feed port 4100 of the viscosity enhancing device 4000.

[0110] Preparation Example

[0111] Example 1

[0112] Inert gas (e.g., nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 70:30) are added into the first reactor and the second reactor respectively, and a catalyst (stannous octoate, the amount of which is 0.002% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 140° C. and 120° C. respectively, and the reaction is carried out at normal pressure for a period of time until The relative molecular weight of the glycolide prepolymer generated in the first reactor is about 15,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 12,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 1 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 60 kPa, the temperature of the inner wall of the scraper is 180 ° C, the speed of the scraper is about 90 rpm, and the materials entering the scraper are The film distributor distributes the material to the inner wall of the film scraper. The scraper scrapes the material on the inner wall of the film scraper continuously and evenly into a uniform liquid film (the average film thickness of the first film scraper is about 650μm, and the average film thickness of the second film scraper is about 520μm), and pushes it downward in a spiral shape. Then, the materials exported from the first and second film scrapers are simultaneously transported to a static mixer (a commercially available SK type static mixer) for copolymerization reaction (wherein, the static mixer is divided into three sections, the temperature of the first section is 170℃, and the temperature of the second section is The temperature is 190° C., the temperature of the third section is 200° C., the time for the material to pass through the first section is about 10 minutes, the time for passing through the second section is about 30 minutes, the time for passing through the third section is about 60 minutes, and the pressure inside the static mixer is normal), so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity-increasing device (for example, a twin-screw extruder with only a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 200° C., the absolute pressure is 500 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0113] Example 2

[0114] This embodiment is basically the same as Embodiment 1, except that, in this embodiment, the static mixer is divided into two sections, the temperature of the first section is 190°C, the temperature of the second section is 200°C, the time for the material to pass through the first section is about 40 minutes, and the time for the material to pass through the second section is about 60 minutes.

[0115] Example 3

[0116] Inert gas (e.g., nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 70:30) are added into the first reactor and the second reactor respectively, and a catalyst (stannous octoate, the amount of which is 0.008% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 156° C. and 142° C. respectively, and the reaction is carried out at normal pressure for a period of time until The relative molecular weight of the glycolide prepolymer generated in the first reactor is about 22,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 20,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 0.8 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 40 kPa, the temperature of the inner wall of the scraper is 195 ° C, the speed of the scraper is about 80 rpm, and the materials entering the scraper are The materials are distributed to the inner wall of the film scraper through the film distributor. The scraper scrapes the materials on the inner wall of the film scraper continuously and evenly into a liquid film of uniform thickness (the average film thickness of the first film scraper is about 620μm, and the average film thickness of the second film scraper is about 450μm), and then the materials are transported downward in a spiral shape. Then, the materials discharged from the first and second film scrapers are simultaneously transported to a static mixer (commercially available SK type static mixer) for copolymerization reaction (wherein, the static mixer is divided into three sections, the temperature of the first section is 160℃, and the temperature of the second section is The temperature is 185°C, the temperature of the third section is 200°C, the time for the material to pass through the first section is about 5 minutes, the time for passing through the second section is about 30 minutes, the time for passing through the third section is about 65 minutes, and the pressure inside the static mixer is normal), so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder with only a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 205°C, the absolute pressure is 200 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0117] Example 4

[0118] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 70:30) are added into the first reactor and the second reactor respectively, and a catalyst (stannous octoate, the amount of which is 0.01% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 165° C. and 170° C. respectively, and the reaction is carried out at normal pressure for a period of time until the first reactor is heated to 150° C. and the second reactor is heated to 150° C. and the reaction is carried out at normal pressure for a period of time until the first ... The relative molecular weight of the glycolide prepolymer generated in the first reactor is about 27,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 26,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 1.2 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 80 kPa, the temperature of the inner wall of the scraper is 190 ° C, the speed of the scraper is about 100 rpm, and the materials entering the scraper The materials are distributed to the inner wall of the film scraper through the film distributor, and the scraper continuously and evenly scrapes the materials on the inner wall of the film scraper into a uniform liquid film (the average film thickness of the first film scraper is about 720μm, and the average film thickness of the second film scraper is about 640μm), and then the materials are transported downward in a spiral shape. Then, the materials discharged from the first and second film scrapers are simultaneously transported to the static mixer (commercially available SK type static mixer) for copolymerization reaction (wherein, the static mixer is divided into three sections, the temperature of the first section is 165℃, and the temperature of the second section is The temperature is 190°C, the temperature of the third section is 205°C, the time for the material to pass through the first section is about 5 minutes, the time for passing through the second section is about 35 minutes, the time for passing through the third section is about 60 minutes, and the pressure inside the static mixer is normal), so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder with only a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 210°C, the absolute pressure is 300 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0119] Example 5

[0120] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 70:30) are added into the first reactor and the second reactor respectively, and a catalyst (stannous octoate, the amount of which is 0.03% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 180° C. and 175° C. respectively, and the reaction is carried out at normal pressure for a period of time until the first reactor is The relative molecular weight of the glycolide prepolymer generated in the reactor is about 35,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 35,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 1.5 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 40 kPa, the temperature of the inner wall of the scraper is 200 ° C, the speed of the scraper is about 120 rpm, and the materials entering the scraper are The film distributor distributes the material to the inner wall of the film scraper, and the scraper scrapes the material continuously and evenly on the inner wall of the film scraper to form a uniform liquid film (the average film thickness of the first film scraper is about 800μm, and the average film thickness of the second film scraper is about 760μm), and then the material is conveyed downward in a spiral shape. Then, the material discharged from the first and second film scrapers is simultaneously transported to a static mixer (commercially available SK type static mixer) for copolymerization reaction (wherein, the static mixer is divided into three sections, the temperature of the first section is 180℃, the temperature of the second section is 200℃, and the temperature of the second section is 100℃). The temperature of the first section is 195° C., the temperature of the third section is 210° C., the time for the material to pass through the first section is about 10 min, the time for passing through the second section is about 30 min, the time for passing through the third section is about 60 min, and the pressure inside the static mixer is normal pressure), so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder only provided with a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 215° C., the absolute pressure is 200 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0121] Example 6

[0122] Inert gas (e.g., nitrogen) is introduced into the first and second reactors to exhaust the air in the reactors, and the raw monomers glycolide and lactide (the molar ratio of the two is 50:50) are added into the first and second reactors respectively, and catalyst (antimony trioxide, the amount of which is 0.06% of the mass of the raw monomers in the corresponding reactor) is added into the first and second reactors respectively, and then the temperature of the first and second reactors is controlled to be 170° C., and the reaction is carried out at normal pressure for a period of time until glycolide generated in the first reactor is The relative molecular weight of the prepolymer is about 26,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 29,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 0.6 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 65 kPa, the temperature of the inner wall of the scraper is 190°C, the speed of the scraper is about 100 rpm, and the material entering the scraper is distributed to the inner wall of the scraper through the film distributor. The scraper continuously and evenly scrapes the material on the inner wall of the scraper into a uniform liquid film (the average film thickness of the first scraper is about 440μm, and the average film thickness of the second scraper is about 470μm), and pushes it downward in a spiral shape]. Then, the materials discharged from the first scraper and the second scraper are simultaneously transported to a static mixer (a commercially available SK type static mixer) for copolymerization reaction (wherein the static mixer is divided into four sections, the temperature of the first section is 168°C, the temperature of the second section is 185°C, the temperature of the third section is 192°C, and the temperature of the fourth section is 196°C). The temperature of the first section is 205° C., the time for the material to pass through the first section is about 5 min, the time for passing through the second section is about 25 min, the time for passing through the third section is about 35 min, the time for passing through the fourth section is about 55 min, and the pressure inside the static mixer is normal pressure), so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder only provided with a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 210° C., the absolute pressure is 400 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0123] Example 7

[0124] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 85:15) are added into the first reactor and the second reactor respectively, and catalysts (i.e., antimony trioxide and tin lactate, the addition amounts of the two are 0.05% and 0.08% of the mass of the raw material monomers in the corresponding reactors) are added into the first reactor and the second reactor respectively, and then the temperatures of the first reactor and the second reactor are controlled to be 130° C. and 158° C. respectively, and the reaction is carried out at normal pressure for a period of time until the first reactor is heated to 100° C. and the reaction temperature is 150° C. The relative molecular weight of the glycolide prepolymer generated in the first reactor is about 26,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 34,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 0.5 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 70 kPa, the temperature of the inner wall of the scraper is 180 ° C, the speed of the scraper is about 90 rpm, and the material entering the scraper is distributed to the inner wall of the scraper through the film distributor. The scraper spreads the material The material is continuously and evenly scraped on the inner wall of the film scraper to form a liquid film of uniform thickness (the average film thickness of the first film scraper is about 380μm, and the average film thickness of the second film scraper is about 430μm), and is pushed downward in a spiral shape]. Subsequently, the materials discharged from the first film scraper and the second film scraper are simultaneously transported to a static mixer (a commercially available SK type static mixer) for copolymerization reaction (wherein the static mixer is divided into five sections, the temperature of the first section is 160°C, the temperature of the second section is 176°C, the temperature of the third section is 190°C, the temperature of the fourth section is 200°C, and the temperature of the fifth section is 200°C. The temperature of the static mixer is 210° C., the time for the material to pass through the first section is about 5 min, the time for passing through the second section is about 10 min, the time for passing through the third section is about 25 min, the time for passing through the fourth section is about 40 min, the time for passing through the fifth section is about 40 min, and the pressure inside the static mixer is normal pressure), so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder only provided with a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 210° C., the absolute pressure is 200 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0125] Example 8

[0126] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 40:60) are added into the first reactor and the second reactor respectively, and catalysts (i.e., stannous octoate and diethyl zinc, the addition amount of the two is 0.1% and 0.05% of the mass of the raw material monomers in the corresponding reactors) are added into the first reactor and the second reactor respectively, and then the temperatures of the first reactor and the second reactor are controlled to be 172° C. and 165° C. respectively, and the reaction mixture is stirred at normal pressure. The reaction was continued for a period of time until the relative molecular weight of the glycolide prepolymer produced in the first reactor was about 40,000, and the relative molecular weight of the lactide prepolymer produced in the second reactor was about 37,000. Then, the materials in the first reactor and the second reactor were respectively introduced into the first scraper and the second scraper at a feed rate of 1.0 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper was 35 kPa, the temperature of the inner wall of the scraper was 195°C, the speed of the scraper was about 100 rpm, and the first scraper and the second scraper .... The material in the film scraper is distributed to the inner wall of the film scraper through the film distributor. The scraper scrapes the material on the inner wall of the film scraper continuously and evenly into a liquid film of uniform thickness (the average film thickness of the first film scraper is about 690μm, and the average film thickness of the second film scraper is about 610μm), and pushes it downward in a spiral shape]. Then, the materials discharged from the first and second film scrapers are simultaneously transported to a static mixer (a commercially available SK type static mixer) for copolymerization reaction (wherein, the static mixer is divided into three sections, the temperature of the first section is 185℃, and the temperature of the second section is 185℃). The temperature of the second section is 195° C., the temperature of the third section is 205° C., the time for the material to pass through the first section is about 20 minutes, the time for passing through the second section is about 30 minutes, the time for passing through the third section is about 40 minutes, and the internal pressure of the static mixer is normal pressure), so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder with only a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 205° C., the absolute pressure is 200 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0127] Example 9

[0128] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 80:20) are added into the first reactor and the second reactor respectively, and a catalyst (stannous octoate, the amount of which is 0.002% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 140° C. and 120° C. respectively, and the reaction is carried out at normal pressure for a period of time until the glycolide generated in the first reactor is The relative molecular weight of lactide prepolymer is about 15,000, and the relative molecular weight of lactide prepolymer generated in the second reactor is about 12,000. Then the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 1 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 60 kPa, the temperature of the inner wall of the scraper is 180 ° C, the speed of the scraper is about 90 rpm, and the material entering the scraper is distributed to the inner wall of the scraper through the film distributor. The scraper The material is continuously and evenly scraped on the inner wall of the film scraper to form a liquid film of uniform thickness (the average film thickness of the first film scraper is about 650μm, and the average film thickness of the second film scraper is about 520μm), and is pushed downward in a spiral shape]. Subsequently, the materials discharged from the first film scraper and the second film scraper are simultaneously transported to the third reactor, and tetrabutyl titanate is transported to the third reactor by a metering pump (the amount of tetrabutyl titanate added is 1.8% of the total mass of the materials discharged from the first film scraper and the second film scraper). The temperature of the third reactor is first controlled to 190℃ for The reaction is carried out until the difference of the intrinsic viscosity of the material in the third reactor before and after 30 minutes is not more than 6, and then the temperature of the third reactor is increased to 210° C. to continue the reaction until the difference of the intrinsic viscosity of the material in the third reactor before and after 10 minutes is not more than 1.5, so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder provided with only a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 220° C., the absolute pressure is 500 Pa, and the devolatilization treatment is carried out for 1 hour), so as to obtain a PLGA copolymer.

[0129] Example 10

[0130] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 80:20) are added into the first reactor and the second reactor respectively, and a catalyst (stannous octoate, the amount of which is 0.008% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 156° C. and 142° C. respectively, and the reaction is carried out at normal pressure for a period of time until the glycolide generated in the first reactor is The relative molecular weight of lactide prepolymer is about 22,000, and the relative molecular weight of lactide prepolymer generated in the second reactor is about 20,000. Then the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 0.8 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 40 kPa, the temperature of the inner wall of the scraper is 195 ° C, the speed of the scraper is about 80 rpm, and the material entering the scraper is distributed to the inner wall of the scraper through the film distributor. The scraper The material is continuously and evenly scraped on the inner wall of the film scraper to form a liquid film of uniform thickness (the average film thickness of the first film scraper is about 620μm, and the average film thickness of the second film scraper is about 450μm), and is pushed downward in a spiral shape]. Subsequently, the materials discharged from the first film scraper and the second film scraper are simultaneously transported to the third reactor, and tetrabutyl titanate is transported to the third reactor through a metering pump (the amount of tetrabutyl titanate added is 2.5% of the total mass of the materials discharged from the first film scraper and the second film scraper). The temperature of the third reactor is first controlled to 200℃ for The reaction is carried out until the difference of the intrinsic viscosity of the material in the third reactor before and after 30 minutes is not more than 6, and then the temperature of the third reactor is increased to 216°C to continue the reaction until the difference of the intrinsic viscosity of the material in the third reactor before and after 10 minutes is not more than 1.5, so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder only provided with a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 220°C, the absolute pressure is 200 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0131] Embodiment 11

[0132] This embodiment is basically the same as Embodiment 10, except that in this embodiment, tetrabutyl titanate is not added to the third reaction kettle.

[0133] Example 12

[0134] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 80:20) are added into the first reactor and the second reactor respectively, and a catalyst (stannous octoate, the amount of which is 0.01% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 165° C. and 170° C. respectively, and the reaction is carried out at normal pressure for a period of time until the glycolide generated in the first reactor is The relative molecular weight of the ester prepolymer is about 12,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 18,000. Then the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 1.2 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 80 kPa, the temperature of the inner wall of the scraper is 190 ° C, the speed of the scraper is about 100 rpm, and the material entering the scraper is distributed to the inner wall of the scraper through the film distributor. The scraper The material is continuously and evenly scraped on the inner wall of the film scraper to form a liquid film of uniform thickness (the average film thickness of the first film scraper is about 720μm, and the average film thickness of the second film scraper is about 640μm), and is pushed downward in a spiral shape]. Subsequently, the materials discharged from the first film scraper and the second film scraper are simultaneously transported to the third reactor, and tetrabutyl titanate is transported to the third reactor through a metering pump (the amount of tetrabutyl titanate added is 0.5% of the total mass of the materials discharged from the first film scraper and the second film scraper). The temperature of the third reactor is first controlled to 180℃ for The reaction is carried out until the difference of the intrinsic viscosity of the material in the third reactor before and after 30 minutes is not more than 6, and then the temperature of the third reactor is increased to 200° C. to continue the reaction until the difference of the intrinsic viscosity of the material in the third reactor before and after 10 minutes is not more than 1.5, so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder only provided with a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 210° C., the absolute pressure is 300 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0135] Embodiment 13

[0136] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 80:20) are added into the first reactor and the second reactor respectively, and a catalyst (stannous octoate, the amount of which is 0.03% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 180° C. and 175° C. respectively, and the reaction is carried out at normal pressure for a period of time until the glycolide generated in the first reactor is The relative molecular weight of the ester prepolymer is about 35,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 35,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 1.5 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 40 kPa, the temperature of the inner wall of the scraper is 200 ° C, the speed of the scraper is about 120 rpm, and the material entering the scraper is distributed to the inner wall of the scraper through the film distributor. The scraper The material is continuously and evenly scraped on the inner wall of the film scraper to form a liquid film of uniform thickness (the average film thickness of the first film scraper is about 800μm, and the average film thickness of the second film scraper is about 760μm), and is pushed downward in a spiral shape]. Subsequently, the materials discharged from the first film scraper and the second film scraper are simultaneously transported to the third reactor, and tetrabutyl titanate is transported to the third reactor through a metering pump (the amount of tetrabutyl titanate added is 1.0% of the total mass of the materials discharged from the first film scraper and the second film scraper). The temperature of the third reactor is first controlled to 186℃ for The reaction is carried out until the difference of the intrinsic viscosity of the material in the third reactor before and after 30 minutes is not more than 6, and then the temperature of the third reactor is increased to 210°C to continue the reaction until the difference of the intrinsic viscosity of the material in the third reactor before and after 10 minutes is not more than 1.5, so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder only provided with a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 215°C, the absolute pressure is 200 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0137] Embodiment 14

[0138] Inert gas (e.g., nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 60:40) are added into the first reactor and the second reactor respectively, and a catalyst (antimony trioxide, the amount of which is 0.06% of the mass of the raw material monomers in the corresponding reactor) is added into the first reactor and the second reactor respectively, and then the temperature of the first reactor and the second reactor is controlled to be 170° C., and the reaction is carried out at normal pressure for a period of time until the glycolide prepolymer generated in the first reactor is The relative molecular weight of the lactide prepolymer produced in the second reactor is about 26,000, and the relative molecular weight of the lactide prepolymer produced in the second reactor is about 29,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 0.6 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 65 kPa, the temperature of the inner wall of the scraper is 190°C, the speed of the scraper is about 100 rpm, and the material entering the scraper is distributed to the inner wall of the scraper through the film distributor, and the scraper continuously The liquid film is then evenly scraped on the inner wall of the film scraper to form a uniform liquid film (the average film thickness of the first film scraper is about 440 μm, and the average film thickness of the second film scraper is about 470 μm), and is pushed downward in a spiral shape]. Subsequently, the materials discharged from the first and second film scrapers are simultaneously transported to the third reactor, and tetraisopropyl titanate is transported to the third reactor through a metering pump (the amount of tetraisopropyl titanate added is 5.0% of the total mass of the materials discharged from the first and second film scrapers). The temperature of the third reactor is first controlled to 195°C for The reaction is carried out until the difference of the intrinsic viscosity of the material in the third reactor before and after 30 minutes is not more than 6, and then the temperature of the third reactor is increased to 210° C. to continue the reaction until the difference of the intrinsic viscosity of the material in the third reactor before and after 10 minutes is not more than 1.5, so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder provided with only a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 220° C., the absolute pressure is 400 Pa, and the devolatilization treatment is carried out for 1 hour), so as to obtain a PLGA copolymer.

[0139] Embodiment 15

[0140] Inert gas (for example, nitrogen) is introduced into the first reactor and the second reactor to exhaust the air in the reactor, and the raw material monomers glycolide and lactide (the molar ratio of the two is 75:25) are added into the first reactor and the second reactor respectively, and catalysts (i.e., antimony trioxide and tin lactate, the addition amounts of the two are 0.05% and 0.08% of the mass of the raw material monomers in the corresponding reactors) are added into the first reactor and the second reactor respectively, and then the temperatures of the first reactor and the second reactor are controlled to be 130° C. and 158° C. respectively, and the reaction is carried out at normal pressure for a period of time until the reaction mixture is heated to 20 ℃ and the reaction temperature is maintained at 130° C. and 158° C. respectively. The relative molecular weight of the glycolide prepolymer generated in the first reactor is about 36,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 40,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 0.5 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 70 kPa, the temperature of the inner wall of the scraper is 180 ° C, the speed of the scraper is about 90 rpm, and the materials entering the scraper are distributed to the scraper through the film distributor. The scraper continuously and evenly scrapes the material on the inner wall of the scraper into a uniform liquid film (the average film thickness of the first scraper is about 380μm, and the average film thickness of the second scraper is about 430μm), and pushes it downward in a spiral shape]. Then, the materials discharged from the first scraper and the second scraper are simultaneously transported to the third reactor, and tetraisopropyl titanate is transported to the third reactor by a metering pump (the amount of tetraisopropyl titanate added is 3.2% of the total mass of the materials discharged from the first scraper and the second scraper). The temperature of the third reactor is first controlled to 1 The reaction is carried out at 95°C until the difference of the intrinsic viscosity of the material in the third reactor before and after 30 minutes is not more than 6, and then the temperature of the third reactor is increased to 210°C to continue the reaction until the difference of the intrinsic viscosity of the material in the third reactor before and after 10 minutes is not more than 1.5, so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder only provided with a devolatilization section) for final polymerization and devolatilization treatment (wherein, the temperature is 218°C, the absolute pressure is 200 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0141] Example 16

[0142] Inert gas (e.g., nitrogen) is introduced into the first and second reaction kettles to exhaust the air in the kettles, and the raw material monomers glycolide and lactide (the molar ratio of the two is 40:60) are added into the first and second reaction kettles, respectively, and catalysts (i.e., stannous octoate and diethyl zinc, the addition amounts of the two are 0.1% and 0.05% of the mass of the raw material monomers in the corresponding reactors) are added into the first and second reaction kettles, respectively, and then the temperatures of the first and second reaction kettles are controlled to be 172° C. and 165° C., respectively, and the reaction is carried out at normal pressure for a period of time until The relative molecular weight of the glycolide prepolymer generated in the first reactor is about 40,000, and the relative molecular weight of the lactide prepolymer generated in the second reactor is about 35,000. Then, the materials in the first reactor and the second reactor are respectively introduced into the first scraper and the second scraper at a feed rate of 1.0 kg / hour for pre-devolatilization treatment [wherein, the absolute pressure in the first scraper and the second scraper is 35 kPa, the temperature of the inner wall of the scraper is 195 ° C, the speed of the scraper is about 100 rpm, and the materials entering the scraper are distributed to the scraper through the film distributor. The scraper continuously and evenly scrapes the material on the inner wall of the scraper into a uniform liquid film (the average film thickness of the first scraper is about 690μm, and the average film thickness of the second scraper is about 610μm), and pushes it downward in a spiral shape]. Then, the materials discharged from the first scraper and the second scraper are simultaneously transported to the third reactor, and tetrabutyl titanate is transported to the third reactor by a metering pump (the amount of tetrabutyl titanate added is 2.2% of the total mass of the materials discharged from the first scraper and the second scraper). The temperature of the third reactor is first controlled to 1 The reaction is carried out at 82°C until the difference in the intrinsic viscosity of the material in the third reactor before and after 30 minutes is not more than 6, and then the temperature of the third reactor is increased to 220°C to continue the reaction until the difference in the intrinsic viscosity of the material in the third reactor before and after 10 minutes is not more than 1.5, so as to obtain a PLGA prepolymer, and then the PLGA prepolymer is transported to a viscosity increasing device (for example, a twin-screw extruder only provided with a devolatilization section) for final polymerization and devolatilization treatment (wherein the temperature is 230°C, the absolute pressure is 200 Pa, and the devolatilization treatment is 1 hour), so as to obtain a PLGA copolymer.

[0143] Comparative Example 1

[0144] Inert gas (e.g., nitrogen) is introduced into the reactor to exhaust the air in the reactor, and the raw monomers glycolide and lactide (the molar ratio of the two is 80:20) are added to the reactor together, and a catalyst (i.e., stannous octoate, the amount of which is 0.01% of the mass of the raw monomer) is added to the reactor, and the reaction is first carried out at normal pressure and 180°C for about 2 hours, then at an absolute pressure of 10kPa and 210°C for 2 hours, then at an absolute pressure of 2kPa and 220°C for 4 hours, and then at an absolute pressure of 600Pa and 230°C for 4 hours, and finally at an absolute pressure of 200Pa and 240°C for 1 hour for devolatilization treatment, and PLGA copolymer is obtained. In this comparative example, coke slag blocks appear at the bottom of the reactor, adhere to the wall of the reactor, and are very difficult to remove.

[0145] Comparative Example 2

[0146] This embodiment is basically the same as Embodiment 3, except that, in this embodiment, the materials in the first reaction kettle and the second reaction kettle are directly transported to a static mixer (a commercially available SK type static mixer) at the same time for copolymerization reaction, thereby eliminating the steps of pre-devolatilization treatment of the glycolide prepolymer and pre-devolatilization treatment of the lactide prepolymer.

[0147] Comparative Example 3

[0148] This embodiment is basically the same as Embodiment 10, except that, in this embodiment, the materials in the first reactor and the second reactor are directly transported to the third reactor at the same time for copolymerization reaction, thereby eliminating the steps of pre-devolatilization treatment of glycolide prepolymer and pre-devolatilization treatment of lactide prepolymer.

[0149] Related test characterization methods in the embodiments:

[0150] The term "yellowness index" as used herein refers to a number calculated from spectrophotometric data that describes the change in color of a test sample from transparent or white to yellow. The test method may be ASTM E313.

[0151] Yellowness Index (YI) Test: Select a copolymer with a smooth surface and no obvious protrusions. Use 3nh's NS series colorimeter to measure the yellowness index (YI) of the product. According to ASTM E313, three measurements are performed under the conditions of 10-degree observation angle, D65 observation light source and reflected light measurement, and the average value is calculated to determine the yellowness index (YI) of the copolymer.

[0152] Weight average molecular weight and its distribution: The sample was dissolved in 5mmol / L sodium trifluoroacetate hexafluoroisopropanol solution to prepare a 0.05-0.3wt% solution. The solution was then filtered through a polytetrafluoroethylene filter with a pore size of 0.4μm. 20μL of the filtered solution was added to the gel permeation chromatography (GPC) injector to determine the molecular weight of the sample. Five molecular weight standards of methyl methacrylate with different molecular weights were used for molecular weight calibration.

[0153] Degradability test: The material to be tested is processed into a sample of 20mm in length × 20mm in height × 20mm in width for degradation experiment. The specific method is as follows:

[0154] Step 1): Take 3 samples, weigh them, record the initial mass as M0, and then place them in a constant temperature drying oven and dry them at 60°C for 24 hours;

[0155] Step 2): Place the three dried samples in three beakers filled with 75°C clean water, and immerse each sample completely in the clean water. Then place the three beakers in three constant temperature and humidity test chambers of the same specifications (the temperature is set at 75°C).

[0156] Step 3): At intervals, take out the samples from the three constant temperature and humidity test chambers, clean them with distilled water, put them in a constant temperature drying oven, vacuum dry them at 75°C for 30 minutes, and weigh them. Record the remaining mass as M'. Then, place the samples in the corresponding beakers and continue the degradation experiment.

[0157] Step 4): Calculate the degradation rate R d , the calculation formula is as follows:

[0158] R d =(M0-M') / M0×100%.

[0159] The degradation rate R to be calculated d When the rate reaches 95%, the experiment is stopped.

[0160] Note: Regarding the selection of sampling interval time period in step 3), in the early stage of the degradation experiment, the sampling interval can be longer (for example, 4 hours, or 6 hours, etc.), and in the middle and late stages of the degradation experiment, the interval can be appropriately shortened (for example, 2 hours, 1 hour, 30 minutes, or 20 minutes, etc.).

[0161] In addition, in step 3), if the original shape of the sample in the beaker has basically disappeared, the following method can be used to measure the mass:

[0162] Take out the beaker from the constant temperature and humidity test box, let it stand, then extract the supernatant to separate the remaining solid phase, and wash the separated remaining solid phase with distilled water, then put it into a constant temperature drying oven, vacuum dry it at 75°C for 30 minutes, then weigh it, and record the mass of the remaining solid phase as M'.

[0163] Tensile strength test: The tensile strength and elongation at break of the sample were measured according to the GB / T 1040.1-2006 test standard (tensile speed is 50 mm / min).

[0164] The yellowness index and weight average molecular weight and distribution of the PLGA copolymers prepared in each embodiment and comparative example are shown in Table 1.

[0165] Table 1

[0166]

[0167] It can be seen from the test results in Table 1 that the yellowness index of the PLGA copolymer prepared based on the present invention is significantly lower than that of the comparative example. It can be seen that the present invention can significantly improve the chromaticity quality of the final PLGA copolymer product and can effectively overcome the yellowing problem of the PLGA product obtained by the existing preparation process.

[0168] Among them, the yellowness index of Example 3 is 12, and the corresponding yellowness index of Comparative Example 2 is 27, and the yellowness index of Example 10 is 15, and the corresponding yellowness index of Comparative Example 3 is 30, which are reduced by about 55.6% and 50%, respectively. Compared with Examples 3 and 10, Comparative Examples 2 and 3 omit the step of pre-devolatilization treatment, that is, the obtained GA prepolymer and LA prepolymer are not pre-devolatilized using a scraper. From the test results in Table 1, it can be seen that although the yellowness index of Comparative Examples 2 and 3 is lower than that of the existing conventional preparation process, i.e., Comparative Example 1, it is still significantly higher than that of Examples 3 and 10. This may be due to the fact that there are still a large number of unreacted lactide monomers or oligomers of lactide monomers in the generated GA prepolymer and LA prepolymer, and during the subsequent copolymerization reaction, some of these substances may be oxidized and deteriorated due to the high temperature and cannot be bonded to the PLGA molecular chain, but remain in the final PLGA product, so that the yellowness index is significantly higher than that of Examples 3 and 10, and also causes an increase in the molecular weight distribution index; the molecular weight distribution uniformity of the PLGA copolymers obtained in Examples 3 and 10 is good.

[0169] In particular, compared with Example 10, Example 11 above omits the addition of tetrabutyl titanate to the third reactor, that is, the GA prepolymer and the LA prepolymer are copolymerized without an ester exchange catalyst. From the test results in Table 1, it can be seen that the yellowness index of Example 11 is significantly lower than that of Comparative Examples 1-3, which may be due to the use of a scraper to pre-devolatilize the generated glycolide prepolymer and lactide prepolymer, which can timely remove the unreacted lactide monomer or oligomer of lactide monomer therein, that is, separate in the form of gas phase and / or gas phase carrying, and be discharged from the gas outlet at the top of the scraper and recovered by the raw material collection unit; so that the content of unreacted lactide monomer or oligomer of lactide monomer remaining in the glycolide prepolymer and lactide prepolymer after the above-mentioned pre-devolatilization treatment will be greatly reduced, which is beneficial to the improvement of the color quality of the final PLGA product. However, since no ester exchange catalyst is added during the copolymerization reaction of the GA prepolymer and the LA prepolymer in the third reactor, it is not conducive to the rapid and effective bonding of the residual unreacted lactide monomer or oligomer of the lactide monomer to the generated PLGA molecular chain. Compared with the static mixer, the heat transfer and stirring effects of the third reactor are limited. The PLGA copolymer generated at the end of the reaction has a sharp increase in viscosity, which is prone to local uneven heating. The heat accumulated there cannot be transferred out in time, which will also lead to thermal oxidation deterioration of the residual unreacted lactide monomer or oligomer of the lactide monomer, affecting the color quality of the final PLGA copolymer product, and also causing the molecular weight distribution of the final PLGA copolymer to become wider.

[0170] In Examples 1-8, the prepolymer treated by pre-devolatilization is introduced into a static mixer for copolymerization. When the prepolymer is moving in the static mixer, multiple splits, merging, and re-splits will occur, that is, the mixing effect is strengthened in a cross-flow manner, which can play a low-shear high-dispersion role on the prepolymer, which is conducive to preventing and eliminating the accumulation of heat in the local area of ​​the material, and can effectively prevent the occurrence of side reactions such as excessive temperature in the local area due to uneven heating in the material and thermal oxidation degradation, thereby ensuring the efficient copolymerization of glycolide prepolymer and lactide prepolymer to obtain a PLGA copolymer with a high molecular weight and a relatively narrow molecular weight distribution. Further, the gradient heating process of the static mixer is conducive to suppressing the rapid change of the viscosity of the reaction system, which can effectively avoid the occurrence of excessive heat accumulation and coking and slagging due to the rapid change of the local viscosity of the reaction system, and can reduce the loss of the reaction material, realize the continuous production of PLGA, and help improve production efficiency.

[0171] The degradability of the PLGA copolymers prepared in each embodiment and comparative example is specifically shown in Table 2.

[0172] Table 2

[0173]

[0174] From the results of the degradation test in Table 2, it can be found that the maximum degradation time difference △t of the three samples in Comparative Example 1 can reach 17 hours, the maximum degradation time difference △t of the three samples in Comparative Example 2 can reach 11 hours, and the maximum degradation time difference △t of the three samples in Comparative Example 3 can reach 13 hours. According to the PLGA copolymer prepared by the present invention, except for the degradation time difference △t of 8 hours in Example 11, the maximum value of the degradation time difference △t of the three samples tested in each example is not more than 5 hours, the degradation time uniformity is good, and excellent degradation stability is shown, which is conducive to the accurate regulation of material degradation and can provide a new idea for the accurate regulation of the degradability of PLGA copolymers.

[0175] This may be because in Examples 1-16, before copolymerizing the glycolide prepolymer and the lactide prepolymer, the two were pre-devolatilized to remove the residual unreacted lactide monomer or oligomer of lactide monomer in time, thereby avoiding the accumulation of such substances in the prepolymer, and minimizing the thermal oxidation deterioration of such substances in the subsequent copolymerization reaction and the residue in the final PLGA copolymer, thereby improving the degradation stability of the final PLGA copolymer, which is conducive to achieving complete degradation of the PLGA copolymer within a specified time (i.e., degradation rate ≥ 95%); while in Example 11, since the copolymerization reaction was carried out in a reactor but no ester exchange catalyst was added, the residual unreacted lactide monomer or oligomer of lactide monomer that was not bonded to the PLGA molecular chain was easily oxidized and deteriorated, and / or was easily decomposed first in the subsequent degradation test, thereby affecting the overall degradation stability, and the degradation time difference △t of the three samples was slightly greater than that of other examples.

[0176] The tensile strength and elongation at break of the PLGA copolymers obtained in each embodiment and comparative example are shown in Table 3 below:

[0177] Table 3

[0178]

[0179] Based on the test results of Table 3 above, it can be seen that compared with the conventional method for preparing PLGA, the heat aging resistance of the PLGA copolymer prepared based on the technology of the present invention has been significantly improved. This is because the steps of pre-devolatilization treatment are omitted in each comparative example, so that the unreacted lactide monomer or oligomer of lactide monomer remaining in the GA prepolymer and LA prepolymer is still relatively large and cannot be removed in time. When the copolymerization reaction is carried out later, some of these substances may be oxidized and deteriorated due to high temperature, and cannot be bonded to the PLGA molecular chain, but remain in the final PLGA product. When subjected to high temperature and high humidity for a certain period of time, it will decompose and generate active free radicals, and induce the PLGA molecular chain to break unexpectedly, so that the mechanical strength of the material deteriorates rapidly, which will seriously affect the heat aging resistance of the material itself.

[0180] For example, the initial tensile strength and initial elongation at break of the PLGA copolymer prepared in Comparative Example 3 are similar to those of Example 10, but after the hot air aging test, the tensile strength and elongation at break of Comparative Example 3 decreased by about 28.9% and 42.1%, while the tensile strength and elongation at break of Example 10 decreased by about 9.5% and 17.9%, respectively, and the heat aging resistance was significantly improved. The initial tensile strength and initial elongation at break of the PLGA copolymer prepared in Comparative Example 2 are similar to those of Example 3, but after the hot air aging test, the tensile strength and elongation at break of Comparative Example 2 decreased by about 22.4% and 38.5%, while the tensile strength and elongation at break of Example 3 decreased by about 10.3% and 17.3%, respectively, and the heat aging resistance was significantly improved.

[0181] In particular, referring to the test results of Examples 10, 11 and the comparative examples in Table 3, although the changes in tensile strength and elongation at break of Example 11 after hot air aging test are better than those of Comparative Examples 1-3, they are still worse than those of Example 10. It is inferred that since the GA prepolymer and the LA prepolymer in Example 11 have been pre-devolatilized before the copolymerization reaction, the residual unreacted lactide monomer or oligomer of lactide monomer in the prepolymer is much less than that in Comparative Examples 1-3, so that its test results are better than those in Comparative Examples 1-3; however, no ester exchange catalyst is used in the later copolymerization reaction of the GA prepolymer and the LA prepolymer, so that the residual unreacted lactide monomer or oligomer of lactide monomer is difficult to be quickly and effectively bonded to the generated PLGA molecular chain. In addition, it is easy to be locally heated unevenly in the reactor, and the heat accumulated there cannot be transferred out in time, resulting in thermal oxidation deterioration of the residual unreacted lactide monomer or oligomer of lactide monomer, and it remains in the final PLGA product, affecting the heat aging resistance of the material itself, and is suitable for application scenarios with lower requirements for heat aging resistance.

[0182] The above description is only a preferred embodiment of the present invention and is not intended to limit the scope of the substantial technical content of the present invention. The substantial technical content of the present invention is broadly defined in the scope of the claims of the application. Any technical entity or method completed by others, if it is exactly the same as that defined in the scope of the claims of the application or an equivalent variation, will be deemed to be included in the scope of the claims.

Claims

1. A preparation device for polylactic acid-glycolic acid block copolymer, characterized in that: The device comprises a first reaction kettle, a second reaction kettle, a first film scraper, a second film scraper, and a third reaction unit and a viscosity increasing device which are sequentially connected in the material feeding direction; The discharge port of the first reactor is connected to the feed port of the first scraper through a material conveying pipeline, and the discharge port of the second reactor is connected to the feed port of the second scraper through a material conveying pipeline; the discharge port of the first scraper and the discharge port of the second scraper are respectively connected to the feed port of the third reaction unit through material conveying pipelines; The first film scraper and the second film scraper both comprise a shell; a rotating shaft, a plurality of scrapers radially connected to the rotating shaft, and a film distributor connected to the feed port are arranged inside the shell; the film distributor is located above the scraper closest to the top of the shell; The top of the shell is provided with an air outlet, and the level of the air outlet is higher than the level of the feed inlet; The device also includes a first raw material collecting unit and a second raw material collecting unit, wherein the first raw material collecting unit is connected to the air outlet of the first scraper through a material conveying pipeline, and the second raw material collecting unit is connected to the air outlet of the second scraper through a material conveying pipeline.

2. The preparation device according to claim 1, characterized in that: The distance between the outer side surface of the scraper and the inner wall of the shell is no more than 5 mm.

3. The preparation device according to claim 1, characterized in that: The distance between the outer side surface of the scraper and the inner wall of the shell is no more than 2 mm.

4. The preparation device according to claim 1, characterized in that: The first film scraper and the second film scraper each further include a heating element disposed outside the housing.

5. The preparation device according to claim 1, characterized in that: The first film scraper and the second film scraper both further include an electric heating sleeve arranged outside the shell.

6. The preparation device according to claim 1, characterized in that: The first raw material collection unit and the second raw material collection unit both contain a gas-liquid separator, a condenser and a recovery tank in sequence according to the material feeding direction.

7. The preparation device according to claim 6, characterized in that: A vacuum pump is provided between the gas-liquid separator and the condenser.

8. The preparation device according to claim 1, characterized in that: A melt pump is provided on a material conveying pipeline connecting the discharge port of the first reactor and the feed port of the first scraper; A melt pump is provided on a material conveying pipeline connecting the discharge port of the second reactor and the feed port of the second scraper; A melt pump is provided on the material conveying pipeline connecting the discharge port of the first scraper and the feed port of the third reaction unit; A melt pump is provided on the material conveying pipeline connecting the discharge port of the second scraper and the feed port of the third reaction unit; The material outlet of the third reaction unit is connected to the material inlet of the viscosity increasing device through a material conveying pipeline, and a melt pump is arranged on the material conveying pipeline.

9. The preparation device according to any one of claims 1 to 8, characterized in that: The third reaction unit is selected from a static mixer or a third reaction kettle, and the third reaction kettle is connected to an ester exchange catalyst sending unit.

10. The preparation device according to claim 9, characterized in that: The transesterification catalyst sending unit comprises a transesterification catalyst storage tank and a material conveying pipeline connecting the transesterification catalyst storage tank and the third reactor, and a metering pump is arranged on the material conveying pipeline.

11. A method for preparing a polylactic acid-glycolic acid block copolymer using the preparation device according to any one of claims 1 to 10, characterized in that: The method comprises the steps of: (1) polymerizing glycolide and lactide in a first reaction kettle and a second reaction kettle to obtain a glycolide prepolymer and a lactide prepolymer, respectively; (2) allowing the obtained glycolide prepolymer to enter a first scraper for pre-devolatilization treatment, and allowing the obtained lactide prepolymer to enter a second scraper for pre-devolatilization treatment; (3) allowing the materials that have been pre-devolatilized in the first scraper and the second scraper to enter the third reaction unit for copolymerization to obtain a polylactic acid-glycolic acid prepolymer; (4) subjecting the polylactic acid-glycolic acid prepolymer to final polymerization and devolatilization in a viscosity increasing device to obtain a polylactic acid-glycolic acid block copolymer.

12. The preparation method according to claim 11, characterized in that: In step (1), the polymerization temperature of glycolide to obtain glycolide prepolymer is 130-190°C; the polymerization temperature of lactide to obtain lactide prepolymer is 120-180°C.

13. The preparation method according to claim 12, characterized in that: Step (1) obtains a glycolide prepolymer with a relative molecular weight of 12,000-40,000; and obtains a lactide prepolymer with a relative molecular weight of 12,000-40,000.

14. The preparation method according to any one of claims 11 to 13, characterized in that: The third reaction unit in step (3) is a static mixer, and the static mixer adopts at least two stages of gradient temperature increase, the temperature range of the first stage is between 160-200°C, and the temperature range of the last stage is between 190-230°C.

15. The preparation method according to any one of claims 11 to 13, characterized in that: The third reaction unit in step (3) is a third reaction kettle, and an ester exchange catalyst is added to the third reaction kettle.

16. The preparation method according to claim 15, characterized in that: The transesterification catalyst is selected from at least one of a titanate catalyst, an organotin catalyst, and an alkali metal alkyl oxide catalyst, and the amount of the transesterification catalyst added is 0.5-5wt% of the total mass of the material discharged from the first scraper and the second scraper.

17. The preparation method according to claim 15, characterized in that: The transesterification catalyst is selected from titanate catalysts.

18. The preparation method according to claim 15, characterized in that: The transesterification catalyst is selected from tetrabutyl titanate and / or tetraisopropyl titanate.

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